EP2952207B1 - Compositions pharmaceutiques pour administration orale à base d'huile - Google Patents

Compositions pharmaceutiques pour administration orale à base d'huile Download PDF

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Publication number
EP2952207B1
EP2952207B1 EP15170455.8A EP15170455A EP2952207B1 EP 2952207 B1 EP2952207 B1 EP 2952207B1 EP 15170455 A EP15170455 A EP 15170455A EP 2952207 B1 EP2952207 B1 EP 2952207B1
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EP
European Patent Office
Prior art keywords
pharmaceutical composition
active agent
bendroflumethiazide
composition according
pharmaceutically active
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Active
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EP15170455.8A
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German (de)
English (en)
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EP2952207A1 (fr
Inventor
Nikesh Engineer
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Essential Pharmaceuticals Ltd
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Essential Pharmaceuticals Ltd
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the present invention relates to a pharmaceutical composition.
  • it concerns a pharmaceutical composition suitable for the oral administration of drug compounds which are typically unstable in aqueous environments, and/or possess an unappealing taste or sensation when swallowed.
  • liquid formulations typically involve preparing oral emulsions (e.g. oil-in-water) of the active agent solubilised in an appropriate solvent system.
  • oral emulsions e.g. oil-in-water
  • US5929030 describes pharmaceutical compositions in which drug compounds are completely dissolved in an oil-based solvent system and then combined with an aqueous solvent to form an oil-in-water oral microemulsion.
  • active agents may be suspended in an appropriate solvent system using stabilising components such as surfactants.
  • stabilising components such as surfactants.
  • US2005/0009908 describes aqueous-based formulations in which a drug nanoparticle is suspended in an aqueous solvent and stabilised by coating the nanoparticle with an oil-based solvent and various surfactants.
  • Oil-based suspensions have also been identified for injectable preparations.
  • WO2012/095438 describes oil-based suspensions comprising crystalline cephalosporin drug compounds which have been uniformly crystallised by means of a diafiltration method (cross-flow filtration) employing membrane filters.
  • a pourable pharmaceutical composition suitable for oral administration comprising at least one pharmaceutically active agent in micronised form, dispersed within a liquid phase which comprises at least one triglyceride of one or more medium-chain fatty acid residues, an anti-caking agent, and up to 2% w/w water, based on the overall composition, wherein the at least one micronised pharmaceutically active agent is bendroflumethiazide or amlodipine, or a pharmaceutically acceptable salt thereof.
  • compositions of this type can be used to formulate active agents which are otherwise unstable in liquid environments, especially in the presence of water.
  • the compositions exhibit excellent storage stability in accordance with ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines.
  • the compositions are appropriate for active agents which are poorly soluble or entirely insoluble in water.
  • active agent refers to a chemical material or compound which, when administered to an organism (human or animal, preferably human), induces a desired pharmacological effect. Included in the meaning of these terms are derivatives of the pharmaceutically active agent such as pharmaceutically acceptable salts.
  • % w/w refers to the relative amount of a component in terms of weight, based on the overall composition.
  • short-chain fatty acid residue refers to linear or branched, saturated or unsaturated aliphatic carboxylic acid residues having a carbon backbone of 1 to 5 carbon atoms. Suitable short-chain fatty acid residues include: formic acid; acetic acid; propionic acid; butyric (butanoic) acid; isobutyric (2-methylbutanoic) acid; valeric (pentanoic) acid; and isovaleric (3-methylbutanoic).
  • medium-chain fatty acid residue refers to linear or branched, saturated or unsaturated (preferably saturated) aliphatic carboxylic acid residues having a carbon backbone of 6 to 12 carbon atoms.
  • Suitable medium-chain fatty acid residues include: caproic (hexanoic) acid; caprylic (octanoic) acid; capric (decanoic) acid; and lauric (dodecanoic) acid.
  • the medium-chain fatty acid residue refers to caprylic (octanoic) acid and/or capric (decanoic) acid.
  • long-chain fatty acid residue refers to linear or branched, saturated or unsaturated aliphatic carboxylic acid residues having a carbon backbone of 13 to 21 carbon atoms. Suitable long-chain fatty acid residues include: myristic (tetradecanoic) acid; palmitic (hexadecanoic) acid; stearic (octadecanoic) acid; linoleic acid; and arachidic (eicosanoic) acid.
  • refined natural lipid oils refers to oils isolated/extracted from natural sources which have been refined to remove impurities such as allergens. Such refined oils may also be bleached and/or deodorised to remove any colouration and/or aroma associated with the natural source. Refined oils may also be processed further by hydrogenation to at least partially reduce the unsaturation in any unsaturated fats/oils which are present. In addition, such oils may be fractionated to provide an oil having a defined range of components, i.e. a specific fraction of the original oil, such as an oil containing only medium-chain fatty acid derivatives. Examples of refined natural lipid oils include coconut oil, castor oil, palm kernel oil, and palm oil (preferably coconut oil).
  • the liquid phase comprises up to 2% w/w water, based on the overall composition. Most preferably, the liquid phase comprises essentially no water, or no detectable amount of water, as determined by the well-known Karl Fischer method. Such low levels of water are advantageous from a stability perspective, since it significantly reduces the likelihood of degradation of the active agent and, in turn, the formation of undesirable impurities. It is also beneficial from a regulatory perspective, since it reduces the number of components in the composition, particularly the need for preservatives, emulsifiers, solubilisers and surfactants that are typically required for aqueous-based compositions.
  • the water in the liquid phase may be free water or water bound to another component of the liquid phase, or a combination of both.
  • bound water may be water held in close association with another component of the liquid phase such as by electrostatic forces.
  • the above preferred embodiments specifying upper limits of water refer to the amount of free water in the pharmaceutical composition, since it is free water which poses a potential stability problem for the active agent.
  • the liquid phase of the pharmaceutical composition is present as a single phase. This is particularly advantageous in embodiments in which there is a low level of water in the composition, such as less than 2% w/w water, based on the overall composition, or where essentially no water is present in the composition and/or where no water has been added to the composition during production.
  • the amount of active agent in the pharmaceutical composition is not particularly limited. It is preferable, nonetheless, that the at least one pharmaceutically active agent is present in a concentration of 0.001% w/w to 5% w/w, based on the overall composition. More preferably, for optimal stability of the composition, the at least one pharmaceutically active agent is present in a concentration of 0.1% w/w to 1% w/w, based on the overall composition.
  • the liquid phase comprises at least one triglyceride having one or more medium-chain fatty acid residues.
  • medium-chain fatty acid residues preferably linear, saturated aliphatic carboxylic acid residues having a carbon backbone of 6 to 12 carbon atoms, more preferably 8 to 10 carbon atoms, e.g. CremerCOOR® MCT 60/40
  • CremerCOOR® MCT 60/40 have been found to be surprisingly advantageous with regard to the long-term storage stability of the composition, and particularly effective in terms of the bioavailability of the active agent.
  • Triglycerides having one or more short-, medium-, or long-chain fatty acid residues may also be preferred.
  • the oil component constitutes the major component of the pharmaceutical composition and may be present in a concentration range of 1% w/w to 99% w/w, based on the overall composition. Preferably, it is present in a concentration range of 10% w/w to 99% w/w, 50% w/w to 99% w/w, 70% w/w to 98% w/w, or 80% w/w to 98% w/w, based on the overall composition.
  • the liquid phase further comprises one or more hydrophilic liquid components selected from glycerine, ⁇ -propylene glycol, ⁇ -propylene glycol, and polyethylene glycol.
  • the hydrophilic liquid component may also be present in a concentration range of 1% w/w to 99% w/w, preferably 10% w/w to 99% w/w, 10% w/w to 70% w/w, or 10% w/w to 50% w/w, based on the overall composition.
  • the active agent of the composition is present in a particulate form, and is dispersed (e.g. suspended) within the oil.
  • the particulate form can be crystalline or amorphous.
  • the particulate form of the active agent is micronised to a desired particle size distribution before incorporation in the composition. Micronisation allows the particle size distribution to be controlled such that the active agent is optimally dispersed within the oil. This facilitates the preparation of a substantially homogenous liquid dispersion.
  • the active agent has an average particle size diameter in the range of 2 nm to 1 ⁇ m, such as 10 nm to 0.9 ⁇ m or 20 nm to 0.8 ⁇ m. Most preferably, the active agent has an average particle size diameter in the range of 100 nm to 0.5 ⁇ m.
  • the average particle size diameter preferably relates to the median particle size diameter, e.g. D50, as determined by laser diffraction methods.
  • Active ingredients for incorporation in the composition can be selected from a variety of known classes of drugs or diagnostic agents, provided they are suitable for oral administration and dispersion in the liquid phase. Active agents which are poorly soluble in aqueous media are favoured, along with active agents possessing an unappealing taste and/or uncomfortable sensation when swallowed.
  • the at least one pharmaceutically active agent is either bendroflumethiazide or amlodipine, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may also comprise one or more pharmaceutically acceptable excipients.
  • excipients refers to substances other than the pharmaceutically active agent which are included in the manufacturing process or are contained in the finished pharmaceutical product dosage form. Excipients are classified by the functions they perform in the pharmaceutical dosage form.
  • the composition may contain one or more sweetening agents, anti-caking agents, surface active agents (e.g. surfactants), viscosity-controlling agents, and/or anti-oxidants.
  • the composition may contain one or more sweetening agents for the purposes of making the composition more palatable.
  • suitable sweetening agents include liquid components based on sucralose, fructose, sorbitol, maltitol, aspartame, cyclamate, and saccharin.
  • sucralose is a particularly preferred sweetening agent.
  • Sweetening agents may be present in the composition in an amount of up to 10% w/w, based on the overall composition, preferably up to 5% w/w.
  • the composition comprises one or more anti-caking agents.
  • Suitable anti-caking agents include magnesium trisilicate, sodium aluminosilicate, calcium aluminosilicate, polydimethylsiloxanes, and colloidal silicon dioxides.
  • the anti-caking agent is one or more colloidal silicon dioxides, particularly anhydrous colloidal silicon dioxides (e.g. Aerosil 200 and/or Aerosil 972, preferably Aerosil 200).
  • the composition when the composition comprises essentially no water or no detectable amount of water, the composition preferably comprises colloidal silicon dioxide. This is because the colloidal silicon dioxide not only helps to provide a substantially homogenous liquid composition of active agent, but is also particularly effective as a viscosity-increasing agent and as a desiccant, i.e. it absorbs residual amounts of water in the composition.
  • the composition may also comprise one or more surface active agents, e.g. surfactants.
  • Suitable surface active agents include anionic, cationic, zwitterionic (ampholytic) and non-ionic surfactants.
  • the surface active agent is a non-ionic surfactant, such as polyoxyethylene hydrogenated castor oils type 40 and/or 60 and polysorbate 80.
  • Such surfactants are effective in stabilising the dispersion of the one or more active agents, and may be useful for providing a homogeneous dispersion (i.e. single phase) if the amount of free water in the pharmaceutical composition exceeds trace levels, 2% w/w, 5% w/w, or 10% w/w, based on the overall composition.
  • the anti-caking agent and the surfactant may be present in the composition in an amount of up to 10% w/w, based on the overall composition, preferably up to 5% w/w.
  • the composition may comprise both an anti-caking agent and a surfactant.
  • a surfactant it has been surprisingly found that the stability of the composition is optimal in the absence of a surfactant.
  • Viscosity-controlling agents may also be present in the composition, where appropriate, in order to provide the desired rheology. Suitable viscosity-controlling agents include colloidal silicon dioxides, methyl-ethyl-propyl cellulose, ethyl cellulose, polyethyleneglycols, or mixtures thereof. Preferably, the viscosity-controlling agent is a polyethyleneglycol. Viscosity-controlling agents may be present in the composition in an amount of up to 5% w/w, preferably in the range of 0.05% w/w to 3% w/w.
  • Stabilising or anti-oxidant agents may also be present in the pharmaceutical composition of the invention.
  • Suitable agents include tocoferols, tocotrienols, retinol, retinal, and retinoic acid.
  • Lipophilic anti-oxidant agents selected from the above are preferred, such as tocoferols. These agents may be present in the composition in an amount of up to 10% w/w, preferably in the range of 0.05% w/w to 8% w/w.
  • the pourable pharmaceutical composition comprises at least one micronised pharmaceutically active agent, suspended within a liquid phase which comprises (preferable consists of) a triglyceride having one or more medium chain fatty acids (preferably a triglyceride of C 6-12 fatty acids, particularly C 8-10 fatty acids such as capric and caprylic fatty acids), a sweetening agent (preferably sucralose), and an anti-caking agent (preferably colloidal silicon dioxide), and wherein the composition comprises essential no water (preferably no detectable amount of water).
  • a surfactant preferably a triglyceride having one or more medium chain fatty acids (preferably a triglyceride of C 6-12 fatty acids, particularly C 8-10 fatty acids such as capric and caprylic fatty acids), a sweetening agent (preferably sucralose), and an anti-caking agent (preferably colloidal silicon dioxide), and wherein the composition comprises essential no water (preferably no detectable amount of water).
  • the composition does not contain a surfactant.
  • composition according to the first aspect for use in therapy.
  • a process for preparing a pharmaceutical composition comprising providing a liquid phase which comprises one or more oils selected from triglycerides having one or more medium-chain fatty acids, and refined natural lipid oils, and up to 2% w/w water, based on the overall composition, and homogeneously dispersing the at least one pharmaceutically active agent in particulate form in the liquid phase.
  • the one or more active agents are micronised to the desired particle size distribution and homogeneously suspended, by means of conventional techniques, in the liquid phase.
  • Example 1 Formulation for a Multi-dose Amlodipine 5mg/5mL lipophilic suspension
  • amlodipine besylate (equal to 5 mg amlodipine), comprising 0.15% by weight, was homogenised in 9,350 mg medium-chain triglycerides, comprising 98.8% by weight. Subsequently, colloidal silicon dioxide 100mg, comprising 1% by weight, was added. The homogenised suspension was analysed to be stable and filled into amber glass bottles.
  • Component Quantity (mg/5ml) Amlodipine besylate micronised 6.93 Medium-chain triglyceride (COOR MCT 60/40 EP) 4.675 Sucralose 1.25 Colloidal Silicon Dioxide (Aerosil 200) 5.0
  • amlodipine 5mg/5ml batch was stored for 3 months at ICH storage conditions 25°C/60%RH and analysed.
  • the in-use stability study was performed according to a pre-defined sampling schedule on amlodipine 5mg/5ml samples stored at 25°C/60%RH.
  • the 29 days in-use stability study was performed on amlodipine 5mg/5ml samples stored at 25°C/60%RH in month 3 of the study. Analysis was performed with validated methods according to pre-defined product specifications and limits for: amlodipine assay, related substances (impurities), HPLC and UV identity, 20°C relative density and closure integrity of the bottle cap.
  • Bottle closure integrity and amlodipine 5mg/5ml suspension appearance was tested each day for a period of 29 days.
  • Bottle closure integrity was tested by turning the bottle upside down for 10 seconds and a visual check if no leaking occurs.
  • Results Analysed results complied with amlodipine 5mg/5ml product specifications and limits.
  • test article solutions were prepared on a lab scale, packed in amber sample bottles, and stored in the dark at room temperature. The following test article solutions were prepared for evaluation:
  • Example 3 Formulation for a Multi-dose Bendroflumethiazide 0.5mg/mL lipophilic suspension
  • the bendroflumethiazide 2.5mg/5ml batch was stored for 3 months at ICH storage conditions 25°C/60%RH and analysed.
  • the in-use stability study was performed according to a pre-defined sampling schedule on bendroflumethiazide 2.5mg/5ml samples stored at 25°C/60%RH.
  • Bottle closure integrity and bendroflumethiazide 2.5mg/5ml suspension appearance was tested each day for a period of 29 days.
  • Bottle closure integrity was tested by turning the bottle upside down for 10 seconds and a visual check if no leaking occurs
  • Results Analysed results complied with bendroflumethiazide 2.5mg/5ml product specifications and limits.
  • test article solutions were prepared on a lab scale, packed in amber sample bottles, and stored in the dark at room temperature. The following test article solutions were prepared for evaluation:

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  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Claims (11)

  1. Composition pharmaceutique versable adaptée à l'administration par voie orale, cette composition renfermant au moins un agent pharmaceutiquement actif sous forme micronisée dispersé dans une phase liquide qui renferme au moins un triglycéride d'au moins un reste d'acide gras à chaîne moyenne, un agent anti-mottant et jusqu'à 2% en poids d'eau, basé sur la composition globale, l'agent pharmaceutiquement actif micronisé étant le bendroflumethiazide ou l'amlodipine, ou l'un de ses sels pharmaceutiquement acceptables.
  2. Composition pharmaceutique conforme à la revendication 1,
    dans laquelle la phase liquide est essentiellement exempte d'eau.
  3. Composition pharmaceutique conforme à la revendication 1 ou à la revendication 2,
    dans laquelle la phase liquide est sous forme monophasée.
  4. Composition pharmaceutique conforme à l'une quelconque des revendications précédentes,
    dans laquelle l'agent pharmaceutiquement actif est présent à une concentration de 0,001 % w/w à 5% w/w basée sur le total de la composition, de sorte que cet agent pharmaceutiquement actif soit présent à une concentration de 0,1% w/w à 1% w/w basée sur le total de la composition.
  5. Composition pharmaceutique conforme à l'une quelconque des revendications précédentes,
    dans laquelle la phase liquide renferme en outre au moins un composant liquide hydrophile choisi parmi les composants suivants : glycérine, α-propylène glycol, β-propylène glycol, et polyéthylène glycol.
  6. Composition pharmaceutique conforme à l'une quelconque des revendications précédentes,
    dans laquelle le triglycéride d'au moins un reste d'acide gras à chaîne moyenne est présent à une concentration de 1% w/w à 99% w/w basée la totalité de la composition, notamment 10% w/w à 99% w/w basée sur le total de la composition.
  7. Composition pharmaceutique conforme à la revendication 5 ou à la revendication 6,
    dans laquelle le composant liquide hydrophile est présent dans une plage de concentration de 10% w/w à 99% w/w basé le total de la composition.
  8. Composition pharmaceutique conforme à l'une quelconque des revendications précédentes,
    dans laquelle l'agent pharmaceutiquement actif a un diamètre de particules situé dans la plage de 2 nm à 1 µm, et en particulier l'agent pharmaceutiquement actif a un diamètre de particules situé dans la plage de 100 nm à 0,5 µm.
  9. Composition pharmaceutique conforme à l'une quelconque des revendications précédentes,
    dans laquelle l'agent anti-mottant est du dioxyde de silicium colloïdal.
  10. Composition pharmaceutique conforme à l'une quelconque des revendications précédentes,
    destiné à être utilisé dans le cadre d'une thérapie.
  11. Procédé de préparation d'une composition pharmaceutique conforme à l'une quelconque des revendications 1 à 9,
    comprenant des étapes consistant à se procurer une phase liquide renfermant au moins un triglycéride d'au moins un reste d'acide gras à chaîne moyenne, un agent anti-mottant, et jusqu'à 2% w/w en poids d'eau basé sur le total de la composition, et disperser de manière homogène l'agent pharmaceutiquement actif sous forme micronisée dans la phase liquide, l'agent pharmaceutiquement actif micronisé étant du bendrofluméthiazide ou de la amlodipine ou l'un de ces sels pharmaceutiquement acceptables.
EP15170455.8A 2014-06-03 2015-06-03 Compositions pharmaceutiques pour administration orale à base d'huile Active EP2952207B1 (fr)

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GB1409869.3A GB2529605B (en) 2014-06-03 2014-06-03 Pharmaceutical composition

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EP2952207A1 EP2952207A1 (fr) 2015-12-09
EP2952207B1 true EP2952207B1 (fr) 2019-03-27

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EP (1) EP2952207B1 (fr)
AU (1) AU2015202991B2 (fr)
DK (1) DK2952207T3 (fr)
GB (1) GB2529605B (fr)
SG (1) SG10201504332VA (fr)

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JP7456933B2 (ja) * 2018-04-11 2024-03-27 シルバーゲイト ファーマシューティカルズ，インク． アムロジピン製剤

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GB2529605A (en) 2016-03-02
GB2529605B (en) 2018-03-21
AU2015202991B2 (en) 2018-09-06
GB201409869D0 (en) 2014-07-16
DK2952207T3 (da) 2019-06-24
AU2015202991A1 (en) 2015-12-17
SG10201504332VA (en) 2016-01-28
EP2952207A1 (fr) 2015-12-09

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